This invention relates generally to drug delivery systems, and more particularly, to a controlled release drug delivery system which is particularly suited for use with first-pass metabolized drugs and which delivers pulsed doses at predetermined time intervals to achieve a bioavailability which is equivalent to immediate release dosage forms administered in divided doses.
A known approach toward effecting the controlled release of orally administered drugs endeavors to achieve a zero order release profile whereby a substantially constant plasma level of the drug is maintained over a predetermined period of time. Although this known approach is suitable for many drugs, it is burdened with several significant disadvantages, and therefore is inappropriate particularly when used with first-pass metabolized drugs and others which are characterized by idiosyncratic pharmacokinetics or pharmacodynamics resulting in reduced bioavailability, altered drug-to-metabolite ratios, altered steady state levels of drug and metabolite, potential food-drug interactions, and altered pharmacodynamic response.
Strategies for reducing the dosing interval of orally administered drugs typically rely on changing the release pattern of the drug from a delivery system, or dosage form, such that the blood level profile of the drug falls within the therapeutic window of the dosing interval. Factoring into this strategy are the pharmacokinetics of the drug and the absorption rate of the drug in the gastrointestinal tract at the site of, and at the time when, the drug is released from the dosage form. The benefits of extended release delivery systems include a decrease in the frequency of dosing and a reduction in the variability of plasma levels of the administered drug over an immediate release dosage form.
In the case of drugs which do not exhibit first pass metabolism, the relationship between the extent of absorption and the bioavailability is linear. Accordingly, changes in bioavailability can be attributed to changes in the extent of absorption. However, in the case of drugs which exhibit first-pass metabolism, the relationship between extent of absorption (or input rate of drug into the portal system) and bioavailability is nonlinear, thereby leading to reduced bioavailability when drugs are administered at very low rates into the gastrointestinal tract.
There is therefore a need for a drug delivery system which yields a reduction in the oral dosing interval of drugs exhibiting first-pass metabolism while simultaneously maintaining bioavailability equivalent to the immediate release dosage form.
In conventional sustained release dosage forms, the bioavailability is compromised by the decreasing release rate. There is therefore a need for a drug dosage delivery system which will release fractions of the total dose at specified times and sites in the GI tract, and thereby minimize the effect of the release rate on the bioavailability.
Propranolol is a first-pass metabolized drug which exhibits non-linearity, or dose dependent bioavailability in the normal therapeutic dosage range. Propranolol hydrochloride, which is available commercially from Ayerst Laboratories, New York, N.Y. under the trademark INDERAL, was the first beta-adrenergic blocking agent to have widespread clinical usage in treating angina and hypertension. The biological half-life of propranolol in man is between two to six hours, and the dosage range is from about 40 to 2000 mg/day typically administered in two to four divided doses.
In order to extend the dosing interval, a controlled release form of propranolol was developed and sold by Ayerst Laboratories under the trademark INDERAL-LA. However, reports indicate that INDERAL-LA performs unsatisfactorily with respect to bioavailability. Although blood levels of propranolol are sustained for a period of 24 hours, the bioavailability is compromised by about 50% as compared to the immediate release dosage form administered in divided doses. It has been determined that such differences in bioavailability are caused by a higher degree of metabolism on first-pass through the liver for the lower release rate, and not incomplete absorption. Since patients on beta-adrenergic blockers are titrated to a particular dosage level given in divided doses, the benefit of once-a-day therapy is offset by possible changes in dosage needed to achieve efficacy.
It is evident from the foregoing that drugs which are eliminated by metabolism and exhibit a non-linear first-pass effect will have drug-to-metabolite level ratios which are dose rate dependent. Consequently, the kinetics of the parent compound and the metabolite are altered by dose rate leading to potentially different clinical responses to the drug. Propranolol, for example, has a bioavailability which varies from 20% to 80% due to dose rate differences. These differences were observed in humans where, for example, the bioavailability of a controlled release form of propranolol was 60% that of the immediate release dosage form, and the peak plasma levels were three-fold lower with the controlled release form leading to potential reduced clinical efficacy. As a result of these deficiencies, INDERAL-LA was required to be the subject of clinical studies to establish efficacy.
In addition to propranolol, other highly metabolized therapeutic agents are suitable for use with the drug dosage delivery system of the present invention. Some commercially available ones of such agents include other beta-adrenergic blockers such as metoprolol and timolol, calcium channel blockers such as verapamil, diltiazem and the anti-epileptic drug phenytoin. Given the large number of drugs which are eliminated by metabolism, there is a great need for an oral dosage form which reduces the relative extent of metabolism.
There are several significant goals which are desired to be realized with the use of a pulsed drug dosage delivery system which delivers doses of a drug at intervals timed to correspond to the administration of a plurality of immediate release doses at predetermined intervals. These include realization of: plasma level time curves equivalent to the immediate release dosage form; clinical efficacy, established through bioavailability, equivalent to the immediate release dosage form; increase in patient compliance as a result of a reduced or simplified dosing schedule; pharmacodynamic equivalence to that of the immediate release dosage form; metabolic rate equivalence to that obtained by conventional dosing schedules so that no unusual accumulation of metabolites or altered metabolic profile will result; accurate programmability of the pulse delay and determination of the fraction of the total dose at each pulse to achieve a variety of predeterminable dosing schedules and permit allowance for circadian rhythms to optimize plasma level time profiles throughout the day and night; and oral delivery of drugs which undergo particularly extensive first-pass metabolism (both gastro-intestinal and hepatic).
In order to accomplish these objectives with a controlled release dosage form, the dosage form must be reproducible, precise, and programmable. However, as a result of the complexity of developing such a system, there is not presently available a drug dosage delivery system of this type. In fact, at the present time, the operating principles of available controlled release dosage forms for oral delivery are based on relatively simple transport models which do not take into account many of the critical factors required to achieve reproducibility and precise programming, such as the physical properties of enteric coating films, including water diffusion into and plasticizer diffusion out of the polymeric coating films, and the consequent time dependent changes in the diffusion coefficient and permeability of the coating; and the time dependent mechanical properties of the coating and its polymer-plasticizer combination such as modulus of elasticity, tensile strength, type of failure (brittle, ductile, necking) or critical strain at failure. In addition, the composition of the core and the conditions under which the coatings are applied to the core can significantly alter the time rate of change of the properties of the coating. Such core variables as osmotic pressure inducing agents, viscosity inducing agents, disintegrants and the presence or absence of lipid materials can influence the swelling rate of the core and therefore the time for failure of the coating.
It is, therefore, an object of this invention to provide a drug delivery system for first-pass metabolized drugs, or other drugs wherein the relationship between extent of absorption and bioavailability is nonlinear, which drug delivery system will have bioavailability equivalent to the immediate release dosage form administered in divided doses.
It is another object of this invention to provide a drug delivery system which reduces oral dosing intervals for first-pass metabolized drugs, and hence improves patient compliance, while maintaining bioavailability equivalent to the immediate release dosage form administered in divided doses.
It is also an object of this invention to provide a drug delivery system for first-pass metabolized drugs which maintains higher plasma levels of drug, and reduces variability in the plasma levels, than currently available controlled release dosage forms.
It is a further object of this invention to provide a drug delivery system for first-pass metabolized drugs which will release an individual dose of drug at specified sites and time in the gastro-intestinal tract so that bioavailability will not be compromised by the decreased release rate of conventional controlled or sustained release dosage forms.
It is additionally an object of this invention to provide a drug delivery system which will provide pulse doses of drugs at precise and reproducible times which correspond to immediate release dosing intervals.
It is yet a further object of this invention to provide a drug delivery system which permits efficacious oral delivery of nonlinear first-pass drugs of the type which are extensively metabolized both gastro-intestinally and hepatically.
It is yet an additional object of this invention to provide a drug delivery system wherein the delivery rate into the portal system is increased, with a corresponding decrease in first pass metabolism.
It is also another object of this invention to provide a method for making a drug delivery device which reliably and precisely programs delivery of pulse doses of drug.
It is a yet further object of this invention to provide a drug delivery system which facilitates accommodation for circadian rhythms in order to optimize plasma level time profiles throughout the day and night.
It is still another object of this invention to provide a method of making a drug delivery system wherein optimal dosing schedules for two, or more drugs, can be achieved by tailoring pulse delivery of each drug to its individual pharmacokinetic and pharmacodynamic properties.
It is also a further object of this invention to provide a drug delivery system which yields a reduction in the oral dosing interval of drugs exhibiting first-pass metabolism while simultaneously maintaining bioavailability equivalent to the immediate release dosage form.
A still further object of this invention is to provide a drug delivery system for oral administration of a drug which reduces the relative extent of metabolism of the administered drug.